RT Journal Article
SR Electronic
T1 Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1380
OP 1392
DO 10.1124/dmd.120.000170
VO 48
IS 12
A1 Marleen J. Meyer
A1 Alzbeta Tuerkova
A1 Sarah Römer
A1 Christoph Wenzel
A1 Tina Seitz
A1 Jochen Gaedcke
A1 Stefan Oswald
A1 Jürgen Brockmöller
A1 Barbara Zdrazil
A1 Mladen V. Tzvetkov
YR 2020
UL http://dmd.aspetjournals.org/content/48/12/1380.abstract
AB The most commonly used oral antidiabetic drug, metformin, is a substrate of the hepatic uptake transporter OCT1 (gene name SLC22A1). However, OCT1 deficiency leads to more pronounced reductions of metformin concentrations in mouse than in human liver. Similarly, the effects of OCT1 deficiency on the pharmacokinetics of thiamine were reported to differ between human and mouse. Here, we compared the uptake characteristics of metformin and thiamine between human and mouse OCT1 using stably transfected human embryonic kidney 293 cells. The affinity for metformin was 4.9-fold lower in human than in mouse OCT1, resulting in a 6.5-fold lower intrinsic clearance. Therefore, the estimated liver-to-blood partition coefficient is only 3.34 in human compared with 14.4 in mouse and may contribute to higher intrahepatic concentrations in mice. Similarly, the affinity for thiamine was 9.5-fold lower in human than in mouse OCT1. Using human-mouse chimeric OCT1, we showed that simultaneous substitution of transmembrane helices TMH2 and TMH3 resulted in the reversal of affinity for metformin. Using homology modeling, we suggest several explanations, of which a different interaction of Leu155 (human TMH2) compared with Val156 (mouse TMH2) with residues in TMH3 had the strongest experimental support. In conclusion, the contribution of human OCT1 to the cellular uptake of thiamine and especially of metformin may be much lower than that of mouse OCT1. This may lead to an overestimation of the effects of OCT1 on hepatic concentrations in humans when using mouse as a model. In addition, comparative analyses of human and mouse orthologs may help reveal mechanisms of OCT1 transport.SIGNIFICANCE STATEMENT OCT1 is a major hepatic uptake transporter of metformin and thiamine, but this study reports strong differences in the affinity for both compounds between human and mouse OCT1. Consequently, intrahepatic metformin concentrations could be much higher in mice than in humans, impacting metformin actions and representing a strong limitation of using rodent animal models for predictions of OCT1-related pharmacokinetics and efficacy in humans. Furthermore, OCT1 transmembrane helices TMH2 and TMH3 were identified to confer the observed species-specific differences in metformin affinity.